SARA Scale Scores Strongly Predictive of Friedreich Ataxia Progression

Caterina Mariotti, MD

Newly published in Annals of Clinical and Translational Neurology, a 4-year follow-up study of patients with Friedreich Ataxia (FA) showed that scores on the Scale for Assessment and Rating of Ataxia (SARA) at study enrollment and age at onset were the key predictive factors of total score disease progression. This analysis suggests a variable sensitivity of the SARA scale at different stages of the disease and offers critical data on population selection that can be interpreted in future clinical trials.¹

The average annual progression rate was 1.60 (95% CI, 1.26–1.95), 1.02 (95% CI, 0.57–1.46), 0.44 (95% CI, −0.11 to –0.98), and 0.14 (95% CI, −0.45 to 0.74) for baseline SARA total scores of 10, 20, 30, and 35 points, respectively. Notably, the average annual progression rate reduced by 0.058 points with each point of the baseline score increase. Also, the median time for an absolute change of SARA was 1 year for baseline scores between 0 and 30, 2 years for scores between 30.5 and 35, and 4 years for scores between 35.5 and 40 points.

The annual number of positive score changes was 57.9 for a baseline score between 0 and 5 points, and gradually decreased to 8.7 for SARA scores between 35.5 and 40 points (P <.0001). The number of negative changes was 2.7 in patients with low baseline scores and 12.6 in those with a high baseline score (P <.0001).

“Our data are consistent with previous observations and confirm that age at onset is the major determinant of FA progression. Age at evaluation also enhanced the prediction of our model, but to a minor extent compared to age at onset, and, interestingly, disease duration was ineffective. Thus, the trajectory of disease progression is not uniform in all patients with FA, and clinical evolution is mainly dependent on earliness of symptoms manifestation,” senior author Caterina Mariotti, MD, head of the Simple Medical Genetics Structure of the Besta Institute, in Milan, Italy, and colleagues wrote.¹ “These observations support the hypothesis that when the disease starts earlier, in the presence of a more severe genetic defect, the faster progression of symptoms reflects a more aggressive form of the disease, occurring in a vulnerable period of growth spurt of childhood and adolescence.”

READ MORE: Phase 2 Trial Shows Increased Frataxin Levels in Friedreich Ataxia Following CT-1601 Treatment

Researchers assessed distribution and longitudinal changes of SARA scores, a primary outcome measure in the European natural history study for FA, and its single items. The SARA scores were analyzed from 502 patients with typical-onset FA participating in the 4-year prospective European FA Consortium for Translational Studies between September 2012 and May 2014. The pattern of disease progression was assessed using linear mixed-effects regression models and was refitted to estimate parameters as well as predict disease progression. Additionally, median time-to-change and rate of score progression using the Kaplan-Meier method and weighted linear regression models were estimated, respectively.

The most frequently observed score corresponded to maximum score for gait (score, 8), stance (6), and both sitting and heel–shin slide (both, 4). The mode values were stable at intermediate score with 2 for speech (maximum score = 6), 1 for finger chase and nose–finger tests (both maximum scores = 4), and 3 for fast alternating hand movements (maximum score = 4). Authors noted that for the item speech, finger chase, nose–finger, and fast alternating hand, the number of negative changes per 100 person-year significantly increased with the increasing of score values (P <.0001).

“Our findings showed that negative changes for gait, stance, sitting, and heel–shin slide were mostly observed at the highest score, and could be interpreted as a random variation occurring at ceiling. On the contrary, in the other items of the scale, negative changes can be observed at intermediate scores values. For these items, the presence of negative changes cannot be because of a ceiling effect, but it may reflect high variability in the performance of the task and in score assignment,” Mariotti et al noted.¹

Authors noted that the longitudinal cohort of data was assessed on a time scale beginning at the inclusion of the study, and that the patient population was very heterogeneous, with many patients having high SARA scores at baseline. In addition, they highlighted that the observational interval was only 4 years and recommended that a longer follow-up could provide more information on SARA progression in favoring other time-dependent models in respect to the linear model. Researchers also noted that the model did not take into account the precise dates of follow-ups or the attrition at subsequent visits.

“SARA scale was developed to detect changes encompassing the entire symptomatic evolution of ataxia, and each item has been intended for scoring specific aspect of disease progression. The large use of the scale in observational and interventional clinical studies provided a great amount of data regarding disease progression of ataxic disorders. The analyses of temporal dynamics of the scale and its items may provide further insights of relevant factors to be taken into account for population selection and result interpretation in future clinical trials,” Mariotti at al noted.¹

REFERENCES
1. Porcu L, Fichera M, Nanetti L, et al. Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset. Ann Clin Transl Neurol. 2023;10.1002/acn3.51886. doi:10.1002/acn3.51886